可溶性CEA诱导结直肠癌中内皮祖细胞归巢促进肿瘤血管新生的机制探讨

项目名称： 可溶性CEA诱导结直肠癌中内皮祖细胞归巢促进肿瘤血管新生的机制探讨

项目编号： No.81472707

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 刘红利

作者单位： 华中科技大学

项目金额： 72万元

中文摘要： 已知内皮祖细胞（EPCs）参与肿瘤发展、转移或复发及血管新生，但是其参与肿瘤血管新生的机制未明。申请人在国家自然科学基金青年基金的研究中首次发现：VEGF可以激活EPCs中PKD1信号，通过HDAC7蛋白磷酸化及其核浆转运，影响EPCs介导的血管形成能力。围绕本项目申请开展的预实验进一步提示：结直肠癌患者外周血中分离的EPCs细胞膜表面存在CEA受体，动物实验中外源性CEA促进EPCs向小鼠皮下肠癌移植瘤周围迁移。本项目据此推测：在结直肠癌患者血液中CEA可与EPCs表面的CEAR结合，促使骨髓源性EPCs归巢至肿瘤部位，通过影响细胞内PKD1及整合素αvβ3信号通路改变EPCs的生物学功能，从而参与诱导肿瘤的血管新生。本项目将有望阐明EPCs 参与肿瘤血管新生的机制，为以EPCs归巢为靶点阻断肿瘤血管生成治疗提供新的策略。

中文关键词： C08_结；直肠肿瘤；内皮祖细胞；血管新生；癌胚抗原

英文摘要： It has been evidenced that endothelial progenitor cells (EPCs) are involved in tumor development, metastasis or recurrence and angiogenesis. However, the molecular mechanisms of tumor angiogenesis process are poorly understood. The applicant in the study of the Youth Fund of National Natural Science Foundation firstly reported that vascular endothelial growth factor (VEGF) phosphorylated the HDAC7 protein through activation of PKD1 signaling pathway in EPCs, which leaded to the HDAC7 protein nucleocytoplasmic transport, thus affecting the ability of angiogenesis mediated by EPCs. Further preliminary research about this project application suggests that the cell surface of EPCs separated from peripheral blood of patients with colorectal cancer expresses CEA receptor, and the exogenous CEA promotes the migration of EPCs to subcutaneous xenografts of colon cancer in mice. Therefore, we assume that soluble CEA in colorectal cancer is an important part of the tumor microenvironment, and blood CEA can be combined with CEAR on the surface of EPCs, prompting bone marrow-derived EPCs homing to the tumor site. Soluble CEA exerts regulatory effects probably by influencing the intracellular PKD1 and integrin αvβ3 signaling pathways, which subsequently changes the biological function of the EPCs, and takes part in the induction of tumor angiogenesis. This project will further elucidate the mechanisms of EPCs involved in tumor angiogenesis in order to provide a new strategy for blocking tumor angiogenesis radically by using the EPCs homing as the target.

英文关键词： Colorectal Cancer;Endothelial progenitor cells;Angiogenesis;Carcinoembryonic Antigen